Dr. LaFleur is a research assistant professor in the department of pharmacotherapy, University of Utah College of Pharmacy Pharmacotherapy Outcomes Research Center.
Nearly one third of women who
develop cancer in the United
States have breast cancer.1
Should this cancer metastasize, most
will eventually have bone involvement.2
Thus, intravenous (IV) bisphosphonates
like pamidronate and zoledronate have
had a large role in breast cancer, as they
treat bone metastases and bone pain.2,3
Now, clinicians also are using bisphosphonates
in these patients for a disease
that is more familiar to most pharmacists—
osteoporosis. Pharmacists need
to understand breast cancer patients'
risks for osteoporosis and recommend
appropriate screening and treatment.
The Connection Between Osteoporosis and Breast Cancer
Breast cancer treatment increases
osteoporosis risk in 2 ways. One cause
is development of chemotherapyinduced
amenorrhea in premenopausal
women.4 Most patients treated with a
common regimen (cyclophosphamide,
methotrexate, and fluorouracil) for estrogen-
receptor?positive (ER+) or negative
breast cancer developed amenorrhea.4
These women have rapid and sustained
bone loss.5 A second cause exists only
in women with ER+ cancers. In these
women, tamoxifen, which has been the
gold standard for adjuvant endocrine
therapy for more than 2 decades, is now
being replaced by aromatase inhibitors
(anastrazole, letrozole, examestane),
which do not protect patients against
osteoporosis as well as tamoxifen. In
fact, their estrogen-suppressing effects
actually increase the risk.6-8 Aromatase
inhibitors reduce cancer recurrence by
as much as an additional 30% over
tamoxifen.9,10 Their risk of serious adverse
events like ischemic stroke, endometrial
cancer, and venous thromboembolism
Screening and Treating Osteoporosis in Breast Cancer
The American Society of Clinical
Oncology (ASCO) recently issued a new
guideline for osteoporosis screening and
treatment in breast cancer.3 It stresses the
need for oncology clinicians to expand
their roles to evaluating bone health
routinely and regularly.3 The breast
cancer?specific guideline was based on
a more general osteoporosis guideline
produced by the US Preventive Services
Task Force (USPSTF).11 The USPSTF recommends
routine bone mineral density
(BMD) screening in women at high risk
for osteoporosis. The USPSTF considers
certain women at high risk—those older
than age 65, or between 60 and 64 and
having other risk factors like a family history
of osteoporosis, or those with a low
body weight (<154 lb) or a prior fragility
fracture. For breast cancer patients,
ASCO adds 2 more high-risk categories:
(1) postmenopausal women (of any
age) receiving aromatase inhibitors, and
(2) younger women with chemotherapy-associated
The Figure shows the ASCO algorithm
for recommending BMD screening,
lifestyle changes, and treatment
interventions in women with and without
these high-risk designations. Like
the USPSTF, ASCO states that clinicians
should encourage all patients to undertake
preventive measures. First, eating a
healthy diet supplemented with calcium and vitamin D maintains
adequate calcium to continually rebuild bone. Second, regular
exercise strengthens bone and maintains high bone density, and,
third, smoking avoidance helps prevent premature bone loss.
These measures are recommended to all patients. High-risk
patients should also receive BMD scans every year, and patients
with BMD T-scores at or below the threshold for osteoporosis (-2.5)
should receive treatment.
ASCO = American Society of Clinical Oncology; BMD = bone mineral density.
Adapted from reference 3.
Osteoporosis Treatments in Breast Cancer
A few of the agents approved by the FDA for osteoporosis prevention
and treatment require special consideration in women
with breast cancer. Raloxifene should be avoided in women
who have had 5 years of treatment with tamoxifen because
of concerns about higher cancer recurrence and mortality
rates.3,12 Teriparatide also is not recommended, because it
caused osteosarcoma in animals.3,13 Estrogen plus progestin is
no longer recommended for osteoporosis prevention because
of the increased risk for serious life-threatening adverse
events, including breast cancer.3,14 Generally, due to strong
safety profiles and a larger pool of evidence supporting their
benefits, bisphosphonates are the treatment of choice in
patients with and without breast cancer.3
As in many symptomless chronic diseases, patient adherence
and persistence with osteoporosis treatment are poor. A
recent meta-analysis showed that only about half of patients
persist with bisphosphonates more than 6 months, and most
discontinue after the first month.15 Poor adherence is alarming;
increasing evidence shows that patients need at least 6
months exposure to reap treatment benefits.16 The newer oral
bisphosphonates' longer dosing intervals may improve patient
adherence.17 For patients who have difficulty persisting with
oral bisphosphonates, even with longer dosing intervals, the
once-yearly bisphosphonate zoledronate may be an alternative.18 Zoledronate lacks the oral bisphosphonates' administration
restrictions but must be infused intravenously; most
physicians' offices are unable to infuse IV drugs. Additionally,
a flu-like infusion reaction occurs after a first dose in about
16% of patients.
Counseling Points for Pharmacists
Because the risk of osteoporosis increases in patients with
breast cancer, pharmacists need to be aware of the guidelines
for preventing fractures, as well as counseling points for these
- Talk with your patients with breast cancer about their risk
for osteoporosis, and encourage those with chemotherapy-
induced amenorrhea or aromatase inhibitor treatment
to seek out yearly BMD screening
- Counsel all patients about the importance of exercising,
eating right, avoiding tobacco smoke exposure, and taking
calcium and vitamin D supplements to strengthen bones
- Recommend a bisphosphonate as first-line treatment in
patients with breast cancer?induced osteoporosis
- Recommend agents with longer dosing intervals for
patients with poor adherence
FDA Approved Therapies for Osteoporosis: Their Role in Breast Cancer Patients
Dose Regimens for Prevention and Treatment
Considerations for Breast Cancer Patients
5 mg by mouth daily
35 mg by mouth weekly
70 mg by mouth weekly
Upper GI irritation, myalgias, arthralgias, rarely osteonecrosis of the jaw
2.5 mg by mouth daily
150 mg by mouth monthly
5 mg by mouth daily
35 mg by mouth weekly
5 mg by intravenous infusion given over 15 minutes yearly
Selective estrogen receptor modulators
60 mg by mouth daily
Do not use after tamoxifen due to occurrence of cross resistance
Hot flushes, leg cramps, deep vein thrombosis
20 U subcutaneously daily
Do not use in breast cancer patients due to osteosarcoma in animal models
Dizziness, leg cramps, hypercalcemia
Estrogen +/- progestin
Do not use in breast cancer or non?breast cancer patients due to adverse effects
Breast tenderness, vaginal bleeding, coronary heart disease, stroke, pulmonary embolism, breast cancer
200 U in one nostril daily
GI = gastrointestinal.
Adapted from reference 3.
- Landis SH, Murray T, Bolden S, Wingo PA. Cancer statistics, 1998. CA Cancer J Clin. 1998;48:6-29.
- Hillner BE, Ingle JN, Berenson JR, et al. American Society of Clinical Oncology guideline on the role of bisphosphonates in breast cancer. American Society of Clinical Oncology Bisphosphonates Expert Panel. J Clin Oncol. 2000;18:1378-91.
- Hillner BE, Ingle JN, Chlebowski RT, et al. American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol. 2003;21:4042-57.
- Bines J, Oleske DM, Cobleigh MA. Ovarian function in premenopausal women treated with adjuvant chemotherapy for breast cancer. J Clin Oncol. 1996;14:1718-29.
- Shapiro CL, Manola J, Leboff M. Ovarian failure after adjuvant chemotherapy is associated with rapid bone loss in women with early-stage breast cancer. J Clin Oncol. 2001;19:3306-11.
- Howell A, Cuzick J, Baum M, et al. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet. 2005;365:60-2.
- Winer EP, Hudis C, Burstein HJ, et al. American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer: status report 2004. J Clin Oncol. 2005;23:619-29.
- Coleman RE. Effect of anastrozole on bone mineral density: 5-year results from the 'Arimidex', Tamoxifen, Alone or in Combination (ATAC) trial. In: Journal of Clinical Oncology, 2006 American Society of Clinical Oncology Annual Meeting Proceedings Part I. 2006;24(18S):511. wwwascoorg/ASCO/Abstracts+%26+Virtual+Meeting/~ Accessed 8 March 2008.
- Goss PE, Ingle JN, Martino S, et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med. 2003;349:1793-802.
- Coombes RC, Hall E, Gibson LJ, et al. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med. 2004;350:1081-92.
- Screening for osteoporosis in postmenopausal women: recommendations and rationale. Am Fam Physician. 2002;66:1430-2.
- Fisher B, Dignam J, Bryant J, Wolmark N. Five versus more than five years of tamoxifen for lymph node-negative breast cancer: updated findings from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial. J Natl Cancer Inst. 2001;93:684-90.
- Cranney A, Guyatt G, Griffith L, Wells G, Tugwell P, Rosen C. Meta-analyses of therapies for postmenopausal osteoporosis. IX: Summary of meta-analyses of therapies for postmenopausal osteoporosis. Endocr Rev. 2002;23:570-8.
- Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA. 2002;288:321-33.
- Kothawala P, Badamgarav E, Ryu S, Miller RM, Halbert RJ. Systematic review and meta-analysis of real-world adherence to drug therapy for osteoporosis. Mayo Clin Proc. 2007;82:1493-501.
- Weycker D, Macarios D, Edelsberg J, Oster G. Compliance with osteoporosis drug therapy and risk of fracture. Osteoporos Int. 2007;18:271-7.
- Lewiecki EM. Long dosing intervals in the treatment of postmenopausal osteoporosis. Curr Med Res Opin. 2007;23:2617-25.
- Black DM, Delmas PD, Eastell R, et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med. 2007;356:1809-22.